Presenter of 2 Presentations
Exploring Hematopoietic Stem and Progenitor Cell Biology Towards New Targeted Therapies for SF3B1mt Myelodysplastic Syndromes with Ring Sideroblasts
ACCELERATED RNA SPLICING DYNAMICS DURING ERYTHROID DIFFERENTIATION AMPLIFY MIS-SPLICING IN SF3B1-MUTANT MDS-RS
Abstract
Background And Aims
Myelodysplastic syndromes with ring sideroblasts (MDS-RS) commonly originate from mutations in the core spliceosome component SF3B1 (SF3B1mt). These induce alternative splicing events that culminate in ineffective erythropoiesis and the development of ring sideroblasts (RS), iron-loaded erythroblasts considered non-viable due to oxidative stress and rapid apoptosis. However, the progressive accumulation of RS in the bone marrow (BM) raises the possibility that SF3B1mt erythroid cells engage yet unexplored molecular pathways to survive. Understanding RS biology is crucial to develop new therapeutic approaches for MDS-RS.
Methods
We investigate SF3B1mt erythroid biology through an integrative multiomics approach, analysing BM mononuclear (MNC) cells and purified RS from MDS-RS patients through flow cytometry, bulk/single-cell RNAseq and semi-quantitative proteomics.
Results
RS retain the ability to undergo erythroid differentiation and enucleate, but suffer from a significant reduction in mitotic activity. This maintained cell biology is accompanied by sustained activation of a major homeostatic response to oxidative/RNA splicing stress. This response includes the overproduction of GDF15 by RS, which we determine enacts a potential negative impact on hematopoietic stem and progenitor cells. Importantly, we find that accelerated splicing dynamics and decreased nonsense-mediated decay during erythroid differentiation reshape SF3B1mt alternative splicing (A, B, C). These effects create a unique transcriptomic landscape in RS, with extensive accumulation of NMD target transcripts and significant dysregulation of TP53 pathway genes (D, E).
Conclusions
We establish RS as an unexpectedly active, disease-contributing and transcriptomically unique cell population. RS biology provides novel insights into MDS-RS and enables further investigation of disease pathobiology, including potential treatment avenues.